Phenobarbital acts on GABA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.

Toxicity

CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may show paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.

Half Life: 53 to 118 hours (mean 79 hours)

Pharmacology

Phenobarbital is capable of producing all levels of CNS mood alteration, from excitation to mild sedation to hypnosis, and deep coma. Over-dosage can produce death. In high enough therapeutic doses, Phenobarbital induces anesthesia. Phenobarbital depresses the sensory cortex, decreases motor activity, alters cerebellar function, and produces drowsiness, sedation, and hypnosis. Phenobarbital-induced sleep differs from physiological sleep. Sleep laboratory studies have demonstrated that Phenobarbital reduces the amount of time spent in the rapid eye movement (REM) phase of sleep or the dreaming stage. Also Stages III and IV sleep are decreased. Following abrupt cessation of Phenobarbital used regularly, patients may experience markedly increased dreaming, nightmares and/or insomnia. Therefore, withdrawal of a single therapeutic dose over 5 or 6 days has been recommended to lessen the REM rebound and disturbed sleep which contribute to drug withdrawal syndrome (for example, decrease the dose from 3 to 2 doses a day for 1 week).

Phenobarbital has little analgesic action at subanesthetic doses. Rather, in sub anesthetic doses, this drug may increase the reaction to painful stimuli. All barbiturates exhibit anticonvulsant activity in anesthetic doses. However, of the drugs in this class, only phenobarbital, mephobarbital, and metharbital are effective as oral anticonvulsants in sub hypnotic doses.

Phenobarbital is a respiratory depressant. The degree of respiratory depression is dependent upon the dose. With hypnotic doses, respiratory depression produced by Phenobarbital is similar to that which occurs during physiologic sleep with slight decrease in blood pressure and heart rate. Studies in laboratory animals have shown that Phenobarbital causes reduction in the tone and contractility of the uterus, ureters, and urinary bladder. However, concentrations of the drug required to produce this effect in humans are not reached with sedative-hypnotic doses.

Phenobarbital does not impair normal hepatic function but has been shown to induce liver microsomal enzymes, thus increasing and/or altering the metabolism of barbiturates and other drugs.

Drug Abuse and Dependence

Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of phenobarbital. As tolerance to phenobarbital develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than two-fold. As this occurs, the margin between an intoxicating dosage and fatal dosage becomes smaller.

Symptoms of phenobarbital dependence are similar to those of chronic alcoholism. If an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood, the use of barbiturates should be suspected. The lethal dose of a barbiturate is far less if alcohol is also ingested. The symptoms of phenobarbital withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of phenobarbital. These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of this drug. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to phenobarbital abuse and dependence include alcoholics and opiate abusers, as well as other sedative- hypnotic and amphetamine abusers.

Drug dependence on phenobarbital arises from repeated administration of the barbiturate or an agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. The characteristics of drug dependence on phenobarbital include: (a) a strong desire or need to continue taking the drug, (b) a tendency to increase the dose, (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects, and (d) a physical dependence on the effects of the drug requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic, and self-limited abstinence syndrome when the drug is withdrawn

Treatment of phenobarbital dependence consists of cautious and gradual withdrawal of the drug. One method involves substituting a 30 mg dose of phenobarbital for each 100 to 200 mg dose that the patient has been taking. The total daily amount of phenobarbital is then administered in 3 to 4 divided doses, not to exceed 600 mg daily. Should signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of phenobarbital may be administered IM in addition to the oral dose. After stabilization on phenobarbital, the total daily dose is decreased by 30 mg a day as long as withdrawal is proceeding smoothly. A modification of this regimen involves initiating treatment at the patient's regular dosage level and decreasing the daily dosage by 10 percent if tolerated by the patient.

Infants physically dependent on phenobarbital may be given a lower dose of phenobarbital at 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, hyperreflexia) are relieved, the dosage of phenobarbital should be gradually decreased and completely withdrawn over a 2-week period.

Contraindications

Phenobarbital is contraindicated in patients with known phenobarbital sensitivity or a history of manifest or latent porphyria.

Administration

Suggested doses of phenobarbital for specific indications are as follows:

a. Pediatric Oral Dosage: preoperative: 1 to 3 mg/kg.

b. Adult Oral Dosage:

1. Daytime sedative: 30 to 120 mg daily in 2 to 3 divided doses.

2. Bedtime hypnotic: 100 to 320 mg.

3. Anticonvulsant: 50 to 100 mg 2 to 3 times daily.

Dosages of phenobarbital must be individualized with full knowledge of their particular characteristics and recommended rate of administration. Factors of consideration are the patient's age, weight, and condition. Parenteral routes should be used only when oral administration is impossible or impractical.

Anticonvulsant use: A therapeutic anticonvulsant level of phenobarbital in serum is 10 to 25 µg/mL. To achieve the blood levels considered therapeutic in children, higher per-kilogram dosages are generally necessary for phenobarbital and most other anticonvulsants. In children and infants, phenobarbital at loading dose of 15 to 20 mg/kg produces blood levels of about 20 µg/mL shortly after administration.

In status epilepticus, it is imperative to achieve therapeutic blood levels of phenobarbital as rapidly as possible. Because a barbiturate-induced depression may occur along with a postictal depression once the seizures are controlled, it is important, therefore, to use the minimal amount required, and to wait for the anticonvulsant effect to develop before administering a second dose.

Phenobarbital has been used in the treatment and prophylaxis of febrile seizures. However, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy.

Special patient population: Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to phenobarbital. Dosage should be reduced for patients with impaired renal function or hepatic disease.

Drug Interactions

Doctors or pharmacist should be aware of and monitor for any possible drug interactions. Do not start, stop, or change the dosage of any medicine before checking with the doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: delavirdine, sodium oxybate, voriconazole.

Some other drowsiness-causing medications may cause serious (possibly fatal) slowed breathing when taken with higher doses of phenobarbital. The patient should tell the doctors or pharmacists, before starting phenobarbital, if he or she also takes other drugs that cause drowsiness such as: medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, amitriptyline, trazodone).

Before using this medication, tell your doctor or pharmacist if you use any other prescription and nonprescription products that cause drowsiness such as certain antihistamines (e.g., diphenhydramine) and anti-seizure drugs (e.g., carbamazepine).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients.

This medication may decrease the effectiveness of combination-type birth control pills. This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Consult your doctor or pharmacist for details.

Precautions

Tolerance and psychological and physical dependence may occur with continuing use. Phenobarbital should be administered with caution, if at all, to patients who are mentally depressed, have suicidal tendencies, or a history of drug abuse. Elderly or debilitated patients may react to Phenobarbital with marked excitement, depression, and confusion.

In patients with hepatic damage, phenobarbital should be administered with caution and initially reduced doses. Phenobarbital should not be administered to patients showing the premonitory signs of hepatic coma.

Prolonged therapy with phenobarbital should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic systems.

Human-data: A retrospective study of 84 children with brain tumors matched to 73 normal controls and 78 cancer controls (malignant disease other than brain tumors) suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumors.

Warning

1. Habit forming: To minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in the dependent person may result in withdrawal symptoms. Phenobarbital should be withdrawn gradually

2. Acute or chronic pain: Caution should be exercised when Phenobarbital is administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of phenobarbital as a sedative in the postoperative surgical period and as an adjunct to cancer chemotherapy is well established.

3. Use in pregnancy: Phenobarbital can cause fetal damage when administered to a pregnant woman. Retrospective case-controlled studies have suggested a connection between the maternal consumption of phenobarbital and higher than expected incidence of fetal abnormalities. Following oral administration, Phenobarbital readily crosses the placental barrier and is distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver, and brain. Withdrawal symptoms occur in infants born to mothers who receive phenobarbital throughout the last trimester of pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

4. Synergistic effects: The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects.

Side Effects

The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients.

More than 1 in 100 patients:

The most common adverse reaction estimated to occur at a rate of 1 to 3 patients per 100 is somnolence.

Less than 1 in 100 patients:

Adverse reactions estimated to occur at a rate of less than 1 in 100 patients listed below, grouped by organ system, and by decreasing order of occurrence are:

If overdose is suspected, contact your local poison control center or emergency room immediately. Symptoms of overdose may include: dizziness, fainting, inability to wake up (coma), slowed breathing, bluish/cold skin.

If you are taking this medication to prevent seizures and miss a dose, take it as soon as you remember unless it is almost time for the next dose. In that case, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

Pregnancy

Pregnancy Category D.

（See Warning 3. Use in pregnancy）

Storage

Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Keep all medicines away from children and pets. Properly discard this product when it is expired or no longer needed.